Liver specific-inhibition of LPCAT3 ameliorates metabolic dysfunction-associated steatotic liver disease

The membrane unsaturation in the liver is associated with abnormal biosynthesis and accumulation of cholesterol and triglycerides, which is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD). The lysophosphatidylcholine acyltransferase 3 (LPCAT3) incorporates arachidonic acid (AA) into the membrane phospholipids and increases the degree of unsaturation. The metabolites of AA are involved in the lipogenesis under high nutrient conditions. However, the mechanistic insights by which LPCAT3 contribute to lipogenesis and MASLD remain unknown. This study found that LPACT3 is upregulated in the liver tissues of diet-induced MASLD and associated with a prominent increase in the arachidonic acid content in the liver, expression of lipogenic genes, and enlargement of liver cells filled with lipid droplets. Most importantly, the prostaglandin E₂ (PGE₂) was notably elevated in the plasma of the high-fat-fed mice. Gene silencing of LPCAT3 notably depleted the AA and PGE₂ in the hepatocytes and attenuated the high-palmitic acid and glucose-induced accumulation of triglycerides and cholesterol. Exogenous addition of PGE₂ markedly reversed the reduced triglyceride and cholesterol accumulation in the LPCAT3 silenced cells. These results indicate that the LPCAT3-arachidonic acid-PGE₂ axis plays a crucial role in lipogenesis in response to excess nutrients in the liver. Most importantly, targeted pharmacologic therapy using GalNac-LPCAT3 siRNA specifically inhibits LPCAT3 expression in the liver and protects against high-fat-induced inflammation, lipogenesis and hepatic dysfunction without affecting hepatic VLDL secretion. This GalNAc-LPCAT3 siRNA biomimetic combined represented safe, effective, and versatile carriers for developing hepatocyte-specific gene therapeutics and preventing MASLD.